The long term research goal of the Principal Investigator (PI) is to establish an internationally recognized research program in the immunobiology of aging using genetically altered mouse models. The specific aims of this proposal are: 1) Provide the salary support and infrastructure to allow the PI a significant increase (50 percent) in effort in mouse pathobiology research. This will necessitate being relieved of time consuming laboratory animal medicine and management obligations, and allow enhanced investigation into the biology of aging, using genetically engineered mouse models; 2) Investigate the role of PKR protein kinase pathway genes in the biology of aging, especially of the immune system, in genetically altered mouse models. The research hypothesis is that the PKR regulatory pathway is a generalized response system for environmental stress, including viruses and free radicals, and is an attempt to conserve cellular resources. Several mouse models are currently available to pursue studies such as the association between PKR expression and translation-associated T cell senescence and proliferation, increased resistance to influenza infection associated with aging, and significance of transcriptional activation of age- related immune dysfunction and inflammation; 3) Characterize genetically altered mouse models of aging, especially in the area of immunobiology, with a focus on mentoring trainees in mouse pathobiology. A vast array of specialized mouse phenotyping expertise and resources are available for pursuing the research goals and providing training to new investigators. This award will relieve the PI from time consuming service obligations and administrative responsibilities, thereby increasing the opportunities for enhancing a research program in the biology of aging, and for mentoring the next generation of mouse pathobiologists.